Tangential-flow filtration system

ABSTRACT

The present invention includes a system and method for transferring a selected solute species from a fluid mixture to a fluid media. The system of the present invention includes a convergent channel for passing a fluid mixture containing a selected species tangentially across the first surface of a porous membrane. A fluid media is directed to flow tangentially over the second surface of the membrane. As the fluid mixture and the fluid media flow on opposite sides of the membrane, the selected species traverses the membrane leaving the fluid mixture and entering the fluid media. The volumetric loss to the fluid mixture associated with the loss of the selected species is compensated for by the convergency of the channel. As a result a constant velocity is maintained over the membrane, maximizing the selectivity of the filtration process.

RELATED APPLICATION

This application in a continuation application claiming priority toapplication Ser. No. 10/121,360, filed Apr. 12, 2002 U.S. Pat. No.6,555,006, which is a continuation of Ser. No. 09/693,701, filed Oct.19, 2000 U.S. Pat. No. 6,387,270, which is continuation of Ser. No.09/501,430, filed Feb. 10, 2000, issued as U.S. Pat. No. 6,221,249 onApr. 24, 2000, which is a continuation of Ser. No. 08/767,909, filedDec. 17, 1996, issued as U.S. Pat. No. 6,054,051 on Apr. 25, 2000, whichclaims the benefit of U.S. provisional Application No. 60/040,912 havingan effective filing date of Jan. 17, 1996, as per the Petition forConversion dated Dec. 5, 1996 under 37 CFR 1.53(b)(2)(ii) from U.S. Ser.No. 08/587,644, filed Jan. 17, 1996, the contents of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention pertains generally to filters which are useful inisolating selected species from fluid mixtures. More specifically, thepresent invention pertains to tangential-flow filters allowing highprotein resolution. The present invention is particularly, but notexclusively, useful as a tangential-flow filter for ultrafiltration ofvarious biological media.

BACKGROUND OF THE INVENTION

In the past, a large number of varying techniques have been developedfor the filtration of fluid mixtures. Many of these techniques requirepassing the fluid mixture through a membrane filter. In general, thesemembrane filtration techniques may be divided into three basiccategories based on filter pore size and filtration pressure. The firstof these categories, known as microfiltration, refers to filters havingrelatively large pore sizes and relatively low operating pressures. Thesecond category, ultrafiltration, refers to filters having intermediatepore sizes and intermediate operating pressures. Finally, the thirdcategory, reverse osmosis, refers to filters having extremely small poresizes and relatively high operating pressures. Predictably,microfiltration techniques are utilized when large solutes, or species,are to be filtered. Ultrafiltration is used when intermediate speciesare to be processed, and reverse osmosis is utilized when extremelysmall species are targeted.

Traditionally, membrane filters have functioned by placing a porousmembrane perpendicularly across the path of a fluid mixture from which aselected species is to be filtered. The fluid mixture flows through themembrane and the selected species is retained by the membrane. A problemgenerally associated with traditional filtration techniques is tendencyof the filter to accumulate solutes from the fluid mixture that is beingfiltered. Accumulation of these solutes creates a layer of solutes onthe filtration membrane and has a tendency to block, or clog, the poresof the membrane decreasing the flow of the fluid mixture, or flux,through the filtration membrane

The decrease in flux attributable to the accumulation of the solutelayer on the filtration membrane may be partially overcome by increasingthe pressure differential, or transmembrane pressure that exists acrossthe filtration membrane. Pressure increases of this type are, however,limited in their effectiveness by the tendency of the filter to becomeincreasingly clogged as the filtration process continues. Eventually, ofcourse, further pressure increases become impractical and the filtrationprocess must be halted and the clogged membrane replaced. This isespecially true when biological or other pressure sensitive species arebeing extracted.

A second problem associated with the accumulation of solutes on thefiltration membrane is the tendency for the solute layer to act as asecondary filter. As a result, as the layer of solutes deposited on thefiltration membrane increases, passage through the filtration membranebecomes limited to smaller and smaller solutes. The tendency for thesolute layer to act as a secondary filter is especially problematicbecause, unlike the decreased flux attributable to the same layer, itcannot be overcome by increasing the transmembrane pressure.

One solution to the problem of membrane blockage has been thedevelopment of tangential-flow filters. Filters of this type employ amembrane which is generally similar to the membrane types employed bytraditional filters. In tangential-flow filters, however, the membraneis placed tangentially to the flow of the fluid mixture to cause thefluid mixture to flow tangentially over a first side of the membrane. Atthe same time, a fluid media is placed in contact with a second surfaceof the membrane. The fluid mixture and the fluid media are maintainedunder pressures which differ from each other. The resulting pressuredifferential, or transmembrane pressure, causes fluid within the fluidmixture, and species within the fluid mixture, to traverse the membrane,leaving the fluid mixture and joining the fluid media.

In operation, the tangential-flow of the fluid mixture over the membranefunctions to prevent solutes within the fluid mixture from settling onthe membrane surface. As a result, the use of tangential-flow filtrationhas proven to be an effective means of reducing membrane blockage formembrane filters. Not surprisingly, then, a wide variety of differingdesigns exist for filters of the tangential-flow type. Unfortunately,even when tangential flow filtration is used, there is still sometendency for solutes to accumulate near the filtration membrane. As isthe case with dead-end filters, the accumulation of solutes degrades thefiltration process, increases the transmembrane pressure and has thetwin effects of decreasing the flux of solutes through the membrane andlimiting traversal through the membrane to smaller solutes. Theseproblems are particularly acute when the species of interest and other,non-desired species within the fluid mixture have similar molecularweights, as is often the case when mixtures of proteins are to befractionated. As a result, tangential flow filtration techniques aregenerally employed only where the species of interest and thenon-desired species have molecular weights which differ by a factor ofat least ten.

A tangential flow filtration which optimizes the solute concentration atthe filtration membrane to increase the ability of the filter to selectbetween similarly sized species is disclosed in U.S. Pat. No 5,256,294entitled “Tangential Flow Filtration Process and Apparatus” which issuedto van Reis and is assigned to the same assignee as the presentinvention. For the device disclosed by van Reis, the transmembranepressure of the filtration process is maintained at a level which isgenerally less than the transmembrane pressure used in traditionaltangential flow filtration systems. More specifically, it has beenobserved that flux in tangential flow filtration systems increases as afunction of transmembrane pressure until the transmembrane pressurereaches a transition point pressure or TPP Once the transmembranepressure reaches TPP, flux is relatively independent of furtherincreases in the transmembrane pressure. Traditional tangential flowfiltration systems have operated with transmembrane pressure whichgenerally equal or exceed TPP. In comparison, the device disclosed byvan Reis maintains the transmembrane pressure of the filtration pressureat a value which is less than TPP. As a result, flux through the deviceof van Reis may be less than the flux achieved by traditional tangentialflow filtration systems. At the same time, however, the ability of thefilter to select between similarly sized species is enhanced.

In spite of the development of tangential flow filtration systems andimproved tangential flow filtration systems, such as the filtrationsystem disclosed by van Reis, there is a continual need for improvedfiltration systems. In particular, there exists a need for filtrationsystems with enhanced abilities to select between similarly sizedsolutes, such as when mixtures of proteins are to be fractionated. Inlight of the above, it is an object of the present invention to providea tangential-flow filtration system for removing solute species from afluid mixture. Yet another object of the present invention is to providea tangential-flow filtration system with an enhanced ability to selectbetween similarly size solutes. Yet another object of the presentinvention is to provide a tangential-flow filtration system which isparticularly suitable for the filtration of protein mixtures. Stillanother object of the present invention is to provide a tangential-flowfiltration system which is relatively simple to use, easy to manufactureand comparatively cost effective.

SUMMARY OF THE PREFERRED EMBODIMENTS

The present invention includes a method and system for transferring aselected solute species from a fluid mixture to a fluid media. Thesystem of the present invention includes a filtration membranepreferably formed as a flat, elongated, sheet having a first surface anda second surface. The filtration membrane has a preferred pore sizechosen to allow the selected solute species to traverse the membrane. Atthe same time, the pore size prevents the passage of solutes that exceedthe size of the selected species.

The system of the present invention also includes a first channel and asecond channel. Both the first channel and the second channel areconstructed to allow fluid to flow tangentially across a surface of thefiltration membrane. More specifically, the first channel is constructedwith an input port and an output port. Fluid, such as the fluid mixture,may enter the first channel at the input port. Between the input portand the output port, the fluid mixture flows tangentially across thefirst surface of the membrane. The fluid mixture then leaves the firstchannel at the output port Similarly, the second channel is constructedwith an input port and an output port. Fluid media supplied at the inputport of the second channel flows tangentially across the second surfaceof the filtration membrane before exiting the second channel at theoutput port. Effectively, as a structural result of the first and secondchannels, an arrangement is created whereby the fluid mixture and fluidmedia flow tangentially on opposite sides of the filtration membrane.Generally, the first and second channels may be formed as part of asingle cassette which also maintains the position of the filtrationmembrane.

The present invention also includes a system of pumps connected to thefirst and second channels. Functionally, the pumping system allows thefluid mixture and the fluid media to be passed through the first andsecond channels. Additionally, the pumping system allows the velocity inthe first and second channels to be selectively controlled. Byselectively controlling the velocities in the first and second channels,and by controlling outlet pressures, a pressure differential, ortransmembrane pressure, is created over the membrane between the fluidmixture in the first channel and the fluid media in the second channel.

For the purposes of the present invention, numerous types of fluid pumpsare adaptable for use in the pumping system. In fact, it may beappreciated that almost any pump that provides the required abilities tomove the fluid mixture and fluid media and to control the pressurewithin the first and second channels may be employed. In practice,however, it will generally be the case that the specific pump typechosen will depend largely on the requirements of the specific filteringoperation.

As described in the preceding paragraphs, the present invention includesa pumping system that is used to pass a fluid mixture and a fluid mediaover opposite surfaces of a porous membrane. The passing of the fluidmixture and the fluid media over opposite sides of the membrane isperformed under pressure and causes the selected species in the fluidmixture to traverse the filtration membrane, leaving the fluid mixtureand joining the fluid media. Preferably, the pressure of the fluidmixture in the first channel and the pressure of the fluid media in thesecond channel are controlled to create a transmembrane pressure whichis less than the transition point pressure (TPP) of the filtrationprocess.

Importantly, for the purposes of the present invention, the firstchannel is constructed to be convergent in the direction of the flow ofthe fluid mixture. Alternatively stated, the first channel ischaracterized by a cross-sectional area which decreases in the directionof the flow of the fluid mixture. As a result, the geometry of the firstchannel effectively compensates for the decreasing volume of the fluidmixture caused by the traversal of the filtration membrane by theselected species. More importantly, however, by compensating for thevolumetric change of the fluid mixture, the convergent geometryestablishes a nearly constant rate of flow for the fluid mixturethroughout the first channel. The constant velocity of the fluid mixturethroughout the first channel optimizes the ability of the filtrationmembrane to select between similarly sized solute species.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of this invention, as well as the invention itself,both as to its structure and its operation, will be best understood fromthe accompanying drawings, taken in conjunction with the accompanyingdescription, in which similar reference characters refer to similarparts, and in which:

FIG. 1 is a schematic diagram of the filtration system of the presentinvention;

FIG. 2 is a schematic diagram of an alternate embodiment of thefiltration system of the present invention;

FIG. 3 is a schematic diagram of the filtration system of the presentinvention, shown in a cascaded configuration; and

FIGS. 4 and 5 are schematic diagrams of the filtration system of thepresent invention, shown in multi-channel configurations.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention includes a method and system for transferring aselected solute species from a fluid mixture to a fluid media. Thefiltration system of the present invention is shown in FIG. 1 andgenerally designated 10. In FIG. 1, it may be seen that the system 10includes a first channel 12 and a second channel 14. The first channel12 has an input end 16 and an output end 18. The first channel 12 ischaracterized by an overall length 20. Additionally, the first channel12 may be seen to have an initial cross-sectional area 22 measured atthe input end 16 and a final cross-sectional area 24 measured at theoutput end 18. Importantly, for purposes of the present invention, theinitial cross-sectional area 22 exceeds the final cross-sectional area24 giving the first channel 12 a narrowing, or converging, quality overlength 20. Like the first channel 12, the second channel 14 has an inputend 26 and an output end 28.

Continuing with FIG. 1, it may be seen that a filtration membrane 30 ispositioned between, and separates, the first channel 12 and the secondchannel 14. The filtration membrane has a first surface 32 and a secondsurface 34. For the purposes of the present invention, the filtrationmembrane 30 has a porous quality and, preferably, is characterized by auniform pore size. The specific material and the specific pore sizechosen for the filtration membrane 30 depends on the size of the solutespecies that will be removed by the filtration system 10. In general,many configurations are possible for first channel 12 and second 14. Forexample, as shown in FIG. 1, for the preferred embodiment of the presentinvention, the first channel 12 and the second channel 14 are configuredin a side-by-side relationship. Alternatively, the first channel 12 andsecond channel 14 may be configured to be coaxially disposed with eitherthe first channel 12 or second channel 14 positioned inside of theother. In fact, any configuration of the first channel 12 and secondchannel 14 that forces the fluid mixture and fluid media to flowtangentially over opposite sides of a filtration membrane and providesthe required convergent configuration for the first channel 12 may beadapted for use in the present invention.

The present invention may also include a feed pump 36 and valve 38. Thefeed pump 36 is connected to an input conduit 40 which connects, in turnto the input end 16 of the first channel 12. For the purposes of thepresent invention, numerous types of fluid pumps are adaptable for useas feed pump 36. In fact, it may be appreciated that almost any pumptype that provides the required abilities to move the fluid mixture andcontrol the pressure within the first channel 12 may be employed.Functionally, the feed pump 36 causes the fluid mixture to pass throughthe input conduit 40 and into the input end 16 of the first channel 12.Once in the first channel 12, the fluid mixture passes along the length20 of the first channel 12 in the direction of the arrow 42. A mixtureoutput conduit 44 is connected at the output end of the first channel 12providing a path for removal of the fluid mixture from the first channel12.

A recirculating pump 46 is also included in the present invention. Therecirculating pump 46 is attached to a recirculation conduit 48 which isconnected, in turn, to the input end 26 of the second channel 14. Therecirculating pump 46 is also connected to a return conduit 50 which isconnected, in turn, to the output end 28 of the second channel 14. Asmay be appreciated by reference to FIG. 1, operation of therecirculating pump 46 forces a stream of fluid media through therecirculation conduit 48 and into the second channel 14. The fluid mediaflows through the second channel 14 in the direction indicated by thearrow 52. The fluid media then enters the return conduit 50 at theoutput end 28 of the second channel 14. The return conduit 50 thenconveys the fluid media back to the recirculating pump 46.

As described in the preceding paragraph, the recirculating pump 46,recirculation conduit 48, second channel 14 and return conduit 50 form acircuit through which fluid media may be continuously circulated. To addor subtract fluid media from the system 10, an extraction pump 54, orvalve 56, are connected to a media output conduit 58.

Operation

In operation of the present invention, feed pump 36 is used to pass afluid mixture containing a selected solute species to be filteredthrough input conduit 40 and into first channel 12. The fluid mixturepasses through first channel 12 in the direction indicated by arrow 42.Within the first channel 12, the fluid mixture passes tangentially overthe first surface 32 of the filtration membrane 30. As the fluid mixturepasses through first channel 12, the feed pump 36 and valve 38 maintainsthe fluid mixture at a predetermined operational pressure. After flowingthe length 20 of the first channel 12, the fluid mixture exits the firstchannel 12 through the mixture output conduit 44. For the purposes ofthe present invention, processing of the fluid mixture may proceed as abatch or continuous process. In cases where a continuous process is tobe utilized, the system 10 shown in FIG. 1 is used to pass the fluidmixture through the first channel 12 as described. In cases where abatch process is to be used, however, the fluid mixture must be forcedto repeatedly flow through the first channel 12. In such cases, thesystem of FIG. 1 may be reconfigured to establish a connection betweenthe mixture output conduit 44 and the feed pump 36.

As the feed pump 36 is causing the fluid mixture to flow through thefirst channel 12, a fluid media is being recirculated in the secondchannel 14. More specifically, the recirculating pump 46 simultaneouslywithdraws fluid media from the return conduit 50 and passes fluid to therecirculation conduit 48. As a result, fluid media is withdrawn from theoutput end of 28 of the second channel 14 and added at the input end 26of the second channel 14. The overall result is that the fluid mediaflows through the second channel 14 in the direction of the arrow 52.Within the second channel 14, the fluid mixture passes tangentially overthe second surface 34 of the filtration membrane 30. As the fluid masspasses through second channel 14, the recirculating pump 46, extractionpump 54 or valve 56 maintain the fluid media at a predeterminedoperational pressure. As a result of the predetermined operationalpressure within the first channel 12 and the predetermined operationalpressure within the second channel 14, a pressure differential, ortransmembrane pressure, is applied across the filtration membrane 30.For the purposes of the present invention, the transmembrane pressure ofthe filtration process is maintained at a value that lies between fiveand one-hundred percent (5-100%) of the transition point pressure (TPP)of the filtration process, where TPP is defined as a pressure abovewhich flux through the filtration membrane 30 is no longer dependent onthe transmembrane pressure.

As the fluid mixture and fluid media flow on opposite sides of thefiltration membrane 30, the selected solute species traverses thefiltration membrane 30, leaving the fluid mixture and joining the fluidmedia. The rate at which the selected species traverses the filtrationmembrane 30 is dependent on a number of factors. These factors include:the particular species, the constituents of the fluid mixture and fluidmedia, the flow rate of the fluid mixture and fluid media, the physicalcharacteristics of the filtration membrane 30, the pressure in the firstchannel 12 and the second channel 14, and the temperature of the fluidmixture and fluid media.

As the selected species traverses the filtration membrane 30, the volumeoccupied by the fluid mixture is effectively decreased. Importantly, inthe present invention, the loss of volume of the fluid mixture withinthe first channel 12 is matched by the convergent geometry of the firstchannel 12. More specifically, for the present invention, the initialcross-section 22, final cross-section 24 and length 20 of the firstchannel 12 are chosen to produce an overall geometry for the firstchannel 12 which compensates for the loss of the fluid volume of thefluid mixture due to traversal of the selected species through thefiltration membrane 30. By compensating for the loss of the selectedspecies, the velocity at which the fluid mixture flows through the firstchannel 12 is maintained at a substantially constant rate throughout thefirst channel 12.

In contrast to the volume of the fluid mixture, the volume occupied bythe fluid media effectively increases as the selected species traversesthe filtration membrane 30. This increase in volume is compensated forby operation of the extraction pump 54 which withdraws excess fluidmedia, now containing the selected solute species, from the system 10.In this fashion, the selected species is removed from the fluid mixtureand added to the fluid media. Generally, it may be appreciated thateither the resulting fluid media (now carrying the selected species) orthe fluid mixture (now stripped of the selected species) may form theend-product of the filtration process.

A first alternate embodiment for the present invention is shown in FIG.2. In FIG. 2, it may be seen that the system 10 of the present inventionincludes all of the elements previously referred to in FIG. 1. In FIG.2, however, an additional filtration membrane 30 a has been added.Filtration membrane 30 a is preferably of the same type and pore size asfiltration membrane 30. Filtration membrane 30 a is also positioned insubstantially the same location as filtration membrane 30. In effect,the combination of filtration membrane 30 and filtration membrane 30 ashown in FIG. 2 provides a double layer filter which replaces the singlelayer filter of FIG. 1 Functionally, inclusion of one or more additionalfilter layers, such as filtration membrane 30 a functions to prevent theminor filter defects associated with commercial grade membrane filtersfrom allowing non-selected species to traverse from the first channel 12to the second channel 14.

The system 10 shown in FIG. 1 as well as the alternate embodiment shownin FIG. 2 are adaptable for use in varying cascaded configurations. Forexample, in FIG. 3, the filtration system 10 of FIG. 1 is replicated toform a two-stage, cascaded, configuration. In more detail, FIG. 3 showsa first filtration system, generally designated 10, and a secondfiltration system, generally designated 10′. Both first filtrationsystem 10 and second filtration system 10′ are fitted with an inputreservoir designated 60 and 60′ respectively. Additionally, theextraction pump 54 shown in FIG. 1, is omitted from system 10 and system10′.

Continuing with FIG. 3, it may be seen that the system 10 and the system10′ are configured to continuously reprocess the fluid mixture.Therefore, mixture output conduit 44 is connected to reservoir 60.Likewise, mixture output conduit 44′ is connected to reservoir 60′. Thisallows the fluid mixture in system 10 and system 10′ to be continuouslyrecirculated through the respective first channel 12 and first channel12′. To cascade the filtration system 10 and the filtration system 10′the media output conduit 58′ is connected to reservoir 60 and the mediaoutput conduit 58 is connected to reservoir 60′. Preferably, the poresize chosen for filtration membrane 30′ is smaller than the pore sizechosen for filtration membrane 30.

The system 10 shown in FIG. 1 as well as the alternate embodiment shownin FIG. 2 are adaptable for use in multi-channel integrated systems. Forexample, in FIG. 4, the basic filtration system 10 of FIG. 1 has beenreplicated to form a multi-channel system 10″. Structurally,multi-channel system 10″ includes a first channel 62 and a last channel64. Between, first channel 62 and last channel 64, system 10″ includes aseries of intermediate channels 66 of which intermediate channels 66 aand 66 b are exemplary. Together, first channel 62, last channel 64 andintermediate channels 66 form a layered sequence of channels 68. Itshould be appreciated that the number of intermediate channels 66 isvariable to suit the ends to which a particular system is directed.Therefore, in FIG. 4, two intermediate channels are included while inFIG. 5, a configuration having only a single intermediate channel isshown. Within the layered sequence 68, first channel 62 and intermediatechannels 66 are configured as recirculating channels and have an inputend 70 and an output end 72. In comparison, last channel 64 isconfigured as a non-recirculating channel which lacks the input end 70and output end of first channel 62 and intermediate channels 66. Lastchannel 64 is, however, formed to include an output 74. Importantly, forthe purposes of the present invention, first channel 62 is formed to beconvergent between input end 70 and output end 72. It is to beappreciated that the convergent geometry shown for first channel 62 isthe same type of convergent geometry as used for first channel 12 ofsystem 10 shown in FIG. 1.

System 10″ also includes a series of filtration membranes 76 of whichmembrane 76 a, 76 b and 76 c are exemplary. Each filtration membrane 76is positioned to between a pair of channels within the layered sequenceof channels 68. For example, filtration membrane 76 a is positioned toseparate first channel 62 and intermediate channel 66 a. Likewise,filtration membrane 76 b is positioned to separate intermediate channel66 a and intermediate channel 66 b. Each filtration membrane 76 isgenerally of the same type as filtration membrane 30 shown in FIG. 1.For the purposes of multi-channel filtration system 10″, however, eachindividual filtration membrane 76 is chosen to have a specific poresize. Additionally, the filtration membranes 76 are arranged so thateach successive filtration membrane 76 has a smaller pore size. In thisfashion, filtration membrane 76 c has a smaller pore size thanfiltration membrane 76 b. Filtration membrane 76 b, in turn, has a poresize that is smaller than the pore size of filtration membrane 76 a.

System 10″ also includes a series of reservoirs 78 of which reservoirs78 a, 78 b and 78 c are exemplary, and a series of recirculation pumps80 of which recirculation pump 80 a, 80 b and 80 c are exemplary. Asshown in FIG. 4, one recirculation pump 80 and one reservoir 78 areconnected to recirculate fluid mixture between the output end 72 andinput end 70 of the recirculating channels included in the layeredsequence of channels 68. For example, recirculation pump 80 a andreservoir 78 a are connected between the output end 72 and the input end70 of first channel 62. Likewise, recirculation pump 80 b and reservoir78 b are connected between the output end 72 and the input end 70 ofintermediate channel 66 a. In this fashion, each recirculation pump 80and reservoir 78 operate to establish a recirculating flow of fluidmixture from the input end 70 to the output end 72 of the recirculatingchannels included in the layered sequence of channels 68.

Continuing with FIG. 4, it may be seen that last channel 64 lacks therecirculating flow of intermediate channels 66. In the case of lastchannel 64, however, it may be seen that output 74 is connected in fluidcommunication with reservoir 78 a.

In operation of system 10″, recirculation pumps 80 a and reservoirs 78 acontinuously recirculate a fluid mixture through first channel 62. Asthe fluid mixture recirculates through first channel 62, fluid andspecies which are. not retained by the filtration membrane 76 a passthrough the filtration membrane 76 a and enter intermediate channel 66a. In this fashion, the fluid mixture recirculated through first channel62 becomes increasingly composed of those species that are retained bythe filtration membrane 76 a.

Importantly, the convergent geometry of first channel 62 compensates forthe loss of the fluid volume of the fluid mixture due to traversal offluid and species through the filtration membrane 76 a. By compensatingfor the loss of the fluid volume, the velocity at which the fluidmixture flows through the first channel 62 is maintained at asubstantially constant rate throughout the first channel 62.

In cooperation with the fluid mixture flow in first channel 62,recirculation pumps 80 and reservoirs 78 operate to continuouslyrecirculate fluid mixture through each intermediate channel 66. As thefluid mixture recirculates through each intermediate channel 66, fluidand species which are not retained by filtration membranes 76 leaveintermediate channel 66 and enter the next intermediate channel 66 orlast channel 64. In this fashion, the fluid mixture recirculated througheach intermediate channel 66 becomes increasingly composed of thosespecies that are retained by a particular filtration membrane 76. Theloss of fluid and species from each intermediate channel 66 is offset byan influx of fluid and species from the channel within the layeredsequence 68 which immediately precedes the particular intermediatechannel 66. In this fashion, the velocity at which the fluid mixtureflows through each intermediate channel 66 is maintained at asubstantially constant rate at all points within the intermediatechannels 66.

Effectively, then, operation of the system 10″ will act to stratify thefluid mixture, placing the largest species in first channel 62, smallerspecies in intermediate channel 66 a and still smaller species in eachsubsequent intermediate channel 66. With the exception of the finalfiltration membrane within the layered sequence 68, recirculation pumps80 preferably maintain the transmembrane pressure over each filtrationmembrane 76 at a value that lies between five and one-hundred percent(5-100%) of the transition point pressure (TPP) of the filtrationprocess. As a result of the controlled transmembrane pressure and theconstant velocity of flow within each channel of layered sequence 68,the ability of the multi-channel system 10″ to select between similarlysized species is enhanced.

While the particular method and system for transferring a selectedsolute species from a fluid mixture to a fluid media as herein shown anddisclosed in detail is fully capable of obtaining the objects andproviding the advantages herein before stated, it is to be understoodthat it is merely illustrative of the presently preferred embodiments ofthe invention and that no limitations are intended to the details ofconstruction or design herein shown other than as described in theappended claims.

1. A tangential-flow filter for selectively transferring a species froma fluid mixture to a fluid media, the filter comprising: a filtrationmembrane having a first surface and a second surface; a cassette formedwith a first channel and a second channel, the first channel beingdisposed to establish a tangential flow of the fluid mixture over thefirst surface of the membrane, the first channel having across-sectional area with the cross-sectional area decreasing in thedirection of the tangential flow, the second channel being disposed toestablish a tangential flow of the fluid media over the second surfaceof the membrane; and means for creating a pressure differential betweenthe fluid mixture in the first channel and the fluid media in the secondchannel to cause the species to traverse the membrane from the fluidmixture to the fluid media.
 2. A tangential-flow filter as recited inclaim 1 further comprising one or more secondary filtration membranes,the secondary filtration membranes disposed between the first surface ofthe filtration membrane and the first channel.
 3. A tangential-flowfilter as recited in claim 1 wherein the first channel and the secondchannel are positioned side-by-side.
 4. A tangential-flow filter asrecited in claim 1 wherein the first channel and the second channel arepositioned coaxially.
 5. A tangential-flow filter as recited in claim 1wherein the velocity of the tangential flow of the fluid mixture issubstantially constant over the length of the first channel.
 6. Atangential-flow filter as recited in claim 1 wherein the pressuredifferential is maintained at a value which is less than the transitionpoint pressure (TPP) of the tangential-flow filter.
 7. A tangential-flowfilter as recited in claim 1 wherein the decrease in the cross-sectionalarea in the direction of the tangential flow is chosen so that thepressure differential is substantially constant over the length of thefiltration membrane.
 8. A tangential-flow filter as recited in claim 1wherein the decrease in the cross-sectional area in the direction of thetangential flow is chosen to compensate for volumetric changes to thefluid mixture caused by the traversal of the filtration membrane by thespecies.
 9. A tangential-flow filter as recited in claim 1 wherein thefiltration membrane is chosen to selectively pass species having amolecular weight of approximately 1 to 1000 kDa.
 10. A tangential-flowfiltration apparatus separating a fluid mixture into species of interestcomprising: a cassette formed with a layered sequence of side-by-sidechannels including a convergent first channel and a last channel, theconvergent first channel and at least one intermediate channelconfigured as recirculating channels having an inlet and an outlet, thelast channel configured as a non-recirculating channel having an outlet;a series of filtration membranes, one filtration membrane positionedbetween each successive pair of channels in the layered sequence witheach successive pair of channels in the layered sequence being separatedby a filtration membrane having a successively smaller pore size; meansfor creating a flow of the fluid mixture between the inlet and theoutlet of each recirculating channel; and means for creating a pressuredifferential between each successive pair of channels in the layeredsequence.
 11. A tangential-flow filtration apparatus as recited in claim10 wherein the cassette is formed to include one intermediate channel.12. A tangential-flow filtration apparatus as recited in claim 10wherein the cassette is formed to include two intermediate channels. 13.A tangential-flow filtration apparatus as recited in claim 10 whereinthe outlet of each recirculating channel is connected in fluidcommunication to the inlet of the channel.
 14. A tangential-flow filteras recited in claim 10 wherein the velocity of the flow of the fluidmixture is substantially constant within each recirculating channel. 15.A tangential-flow filter as recited in claim 10 wherein the pressuredifferential between each successive pair of recirculating channels inthe layered sequence is maintained at a value which is less than thetransition point pressure (TPP) of the tangential-flow filter.
 16. Atangential-flow filter as recited in claim 10 wherein the convergentfirst channel is dimensioned so that the pressure differential betweenthe convergent first channel and the intermediate channel issubstantially constant over the length of the filtration membranepositioned between the convergent first channel and the intermediatechannel by the species.
 17. A tangential-flow filter as recited in claim10 wherein the convergent first channel is dimensioned to compensate forvolumetric changes to the fluid mixture caused by the traversal of thefiltration membrane positioned between the convergent first channel andthe intermediate channel by the species.
 18. A process for selectivelytransferring a species from a fluid mixture, comprising the steps of:passing the fluid mixture through a channel for tangential flow over afirst surface of a primary filtration membrane, the channel shaped tohave a cross-sectional area, the cross-sectional area decreasing in thedirection of the tangential flow; passing a fluid media for tangentialflow over a second surface of the primary filtration membrane, thetangential flow of the fluid mixture adjacent to the tangential flow ofthe fluid media; and creating a pressure differential between the fluidmixture in the channel and the fluid media to cause the species totraverse the primary filtration membrane from the fluid mixture to thefluid media.
 19. A process as recited in claim 18 further comprising thestep of filtering the fluid media by tangential flow filtration over asecondary filtration membrane, the secondary filtration membrane havinga smaller pore size.
 20. A tangential-flow filter for selectivelytransferring a species from a fluid mixture to a fluid media, the filtercomprising: filtration means having a first surface and a secondsurface; channeling means for causing the mixture to flow tangentiallyat a first pressure over the first surface of the filtration means, thechanneling means having a length, the channeling means shaped todecrease from a first cross-sectional area to a second cross-sectionalarea over the length of the channeling means; means for causing thefluid media to flow tangentially at a second pressure over the secondsurface of the filtration means, the first pressure and the secondpressure creating a pressure differential over the filtration means, thepressure differential causing the species to traverse the filtrationmeans from the fluid mixture to the fluid media; means for creating apressure differential between the mixture and the fluid media, thepressure differential causing the species to traverse the filtrationmeans from the fluid mixture to the fluid media.
 21. A tangential-flowfilter as recited in claim 20 wherein the filtration means comprises afiltration membrane.
 22. A tangential-flow filter as recited in claim 21wherein the first cross-sectional area and the second cross-sectionalarea are chosen so that the decrease of cross-sectional area compensatesfor volumetric changes to the fluid mixture caused by the traversal ofthe membrane by the species.
 23. A tangential-flow filter as recited inclaim 21 wherein tangential flow of the fluid mixture is substantiallyconstant over the length of the channeling means.
 24. A tangential-flowfilter as recited in claim 21 wherein the first area and the second areaare chosen so that the pressure differential is substantially constantover the length of the channeling means.
 25. A tangential-flow filter asrecited in claim 20 wherein the filtration means comprises a pluralityof filtration membranes.
 26. A tangential-flow filter as recited inclaim 20 wherein the filtration means is chosen to selectively passspecies having a molecular weight of approximately 1 to 1000 kDa.